Atorvastatin Attenuates Ischemia/Reperfusion-Induced Hippocampal Neurons Injury Via Akt-nNOS-JNK Signaling Pathway
Atorvastatin Attenuates Ischemia/Reperfusion-Induced Hippocampal Neurons Injury Via Akt-nNOS-JNK Signaling Pathway
复制标题
阿托伐他汀通过 Akt-nNOS-JNK 信号通路减轻缺血/再灌注引起的海马神经元损伤
DOI：
10.1007/s10571-016-0412-x
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发表时间：
2017-05-01
影响因子：
4
通讯作者：
Zhang, Fayong
中科院分区：
文献类型：
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作者：
Shao, Sen;Xu, Mingwei;Zhang, Fayong
缺血性脑损伤导致细胞凋亡，如选择性脆弱区域的迟发性神经元死亡，这可能进一步导致不可逆的损伤。以往的研究表明，海马CA 1区的神经元对缺血性损伤特别敏感。阿托伐他汀（Atorvastatin，ATV）可改善脑卒中后认知功能障碍，但其确切的神经保护机制尚不清楚。因此，本研究旨在探讨ATV对脑缺血再灌注损伤的神经保护机制。本研究采用四血管闭塞法建立大鼠脑缺血模型。将大鼠分为假手术组、缺血再灌注组、缺血再灌注+ATV组、缺血再灌注+ATV+LY组、缺血再灌注+SP 600125组。甲酚紫染色观察海马CA 1区神经元死亡情况。采用免疫印迹法检测相关蛋白的表达。结果表明，ATV对海马CA 1区锥体神经元有明显的保护作用。ATV可增加蛋白激酶B（Akt 1）和nNOS的磷酸化，降低JNK 3和c-Jun的磷酸化，进一步抑制caspase-3的活化。ATV的上述作用可被Akt 1抑制剂LY 294002逆转。JNK抑制剂SP 600125预处理可降低JNK 3和c-Jun的磷酸化水平，进一步抑制caspase-3的活化。本研究结果提示Akt介导的nNOS磷酸化可能通过抑制JNK 3信号通路参与ATV对缺血性脑损伤的神经保护作用，为脑卒中的治疗提供了新的实验依据。
Ischemia-induced brain damage leads to apoptosis like delayed neuronal death in selectively vulnerable regions, which could further result in irreversible damages. Previous studies have demonstrated that neurons in the CA1 area of hippocampus are particularly sensitive to ischemic damage. Atorvastatin (ATV) has been reported to attenuate cognitive deficits after stroke, but precise mechanism for neuroprotection remains unknown. Therefore, the aims of this study were to investigate the neuroprotective mechanisms of ATV against ischemic brain injury induced by cerebral ischemia reperfusion. In this study, four-vessel occlusion model was established in rats with cerebral ischemia. Rats were divided into five groups: sham group, I/R group, I/R+ATV group, I/R+ATV+LY, and I/R+SP600125 group. Cresyl violet staining was carried out to examine the neuronal death of hippocampal CA1 region. Immunoblotting was used to detect the expression of the related proteins. Results showed that ATV significantly protected hippocampal CA1 pyramidal neurons against cerebral I/R. ATV could increase the phosphorylation of protein kinase B (Akt1) and nNOS, diminished the phosphorylation of JNK3 and c-Jun, and further inhibited the activation of caspase-3. Whereas, all of the aforementioned effects of ATV were reversed by LY294002 (an inhibitor of Akt1). Furthermore, pretreatment with SP600125 (an inhibitor of JNK) diminished the phosphorylation of JNK3 and c-Jun, and further inhibited the activation of caspase-3 after cerebral I/R. Taken together, our results implied that Akt-mediated phosphorylation of nNOS is involved in the neuroprotection of ATV against ischemic brain injury via suppressing JNK3 signaling pathway that provide a new experimental foundation for stroke therapy.